DESCRIPTION (Applicant's Abstract): Evidence from a wide variety of fields indicates that both neural modulation of immunity and immune-mediated communication with the CNS represent important pathways of biological signalling with importance to human health and disease throughout life. With the normal aging process the frequency of viral infections, cancer, and autoimmune diseases increases, cell-mediated immune responses decline, degenerative brain changes occur, and psychosocial factors appear to have a greater impact of health. Recent studies from this laboratory have demonstrated a striking decrease in the presence of noradrenergic (NA) nerve fibers and norepinephrine (NE) availability in spleens from aged rodents that correlate well with the decline in T cell mediated immunity that occurs with aging. Concomitant with this age-related decline in NA splenic innervation, the density of specific immune cell populations in compartments that receive abundant NA nerve fibers in the young adult spleen also shows a progressive decline with age. Collectively, these findings suggest a possible relationship between age-associated denervation of NA innervation of secondary lymphoid organs and age-associated immunosenescence. The present proposal is designed to further investigate the dynamics of NA innervation in the aged spleen and its relationship to immunocompetence in aged rodents. Specific Aim 1 addresses the availability of NE for interaction with splenocytes and the ability of splenocytes to respond to NA sympathetic signals in aged rat. Specific Aim 2 proposes to determine whether loss of NA nerve fibers in old spleens result from (1) a retraction of NA nerve fibers with age, (2) a metabolic deficit that depletes NE from nerve terminals, or (3) cell death of NA sympathetic neurons in the superior mesenteric-celiac ganglionic complex. Specific Aim 3 is to examine the capability of the old spleen to maintain NA innervation. Specific Aim 4 is to investigate the effect of chronic environmental antigenic stimulation on the full expression of age-associated decline in NA innervation of the spleen. These studies examine a vital part of the neural-immune link, efferent autonomic outflow to lymphoid organs, at a time when cell mediated immunity is compromised. They will provide a better understanding of the functional consequences of diminished neural signals on immune function in aged rodents and may ultimately lead to new therapeutic approaches for immunomodulation in conditions of compromised immune function through pharmacologic manipulation of neurotransmitter systems.